This proposal will explore functional, biochemical, and structural considerations in both large and small coronary vessel ischemia. The coronary circulation will be studied in terms of functional vascularity, arborization, and vascular patency during the cardiac cycle. These have implications for ischemic events at the microvascular level. Large vessel coronary ischemia will be studied in terms of its effects on the extracellular collagen matrix. In particular, myocardial properties in the post-ischemic dysfunctional myocardium ("stunned myocardium") will be related to ultrastructural and biochemical analyses of the collagen matrix. The first area of study relates to observations that indicate coronary arterioles in the epicardial layer arborize to a greater extent than those in the endocardium. This unique anatomic scheme has definite functional consequences in terms of transmural patterns of blood flow and necrosis. A preliminary model of such an arborization scheme has been constructed and physiological insights are provided for experimental testing. Experimental studies will be performed to characterize the vascular tree at different levels of the circulation. The second and related area of study will address the nature of the extravascular coronary resistance. Cardiac contraction affects the lumenal patency of the intramyocardial exchange vessels to an unknown degree. Blood flow is significantly compromised in the endocardial layer during coronary hypoperfusion. The basis for this greater resistance in the endocardial layer may be due to: lumenal narrowing without collapse, or complete collapse and derecruitment. Studies will be performed to determine which of these mechanisms are operative during coronary hypoperfusion. Continuous patency throughout the cardiac cycle would have obvious physiological advantages. The third area of study will deal with the "stunned" myocardium. We have shown that ischemic insults which are not severe enough to cause cellular necrosis, nevertheless have profound effects on the extracellular collagen. Studies are planned to relate the loss of these support structures to mechanical indices of diastolic function. We hypothesize that loss of the support structures result in irreversible plastic changes in the myocardium. This would have implications with regards to heart size, geometry, and function. We plan to correlate ultrastructure, collagen content, collagenase activity in the stunned myocardium, and relate these data to changes in dystocial function.